Preleukaemic clonal haemopoiesis and risk of therapy-related myeloid neoplasms: a case-control study

doi:10.1016/S1470-2045(16)30626-X

The Lancet Oncology

Volume 18, Issue 1, January 2017, Pages 100-111

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https://doi.org/10.1016/S1470-2045(16)30626-X Get rights and content

Summary

Background

Therapy-related myeloid neoplasms are secondary malignancies that are often fatal, but their risk factors are not well understood. Evidence suggests that individuals with clonal haemopoiesis have increased risk of developing haematological malignancies. We aimed to identify whether patients with cancer who have clonal haemopoiesis are at an increased risk of developing therapy-related myeloid neoplasms.

Methods

We did this retrospective case-control study to compare the prevalence of clonal haemopoiesis between patients treated for cancer who later developed therapy-related myeloid neoplasms (cases) and patients who did not develop these neoplasms (controls). All patients in both case and control groups were treated at MD Anderson Cancer Center (Houston, TX, USA) from 1997 to 2015. We used the institutional medical database to locate these patients. Patients were included as cases if they were treated for a primary cancer, subsequently developed therapy-related myeloid neoplasms, and had available paired samples of bone marrow from the time of therapy-related myeloid neoplasm diagnosis and peripheral blood from the time of primary cancer diagnosis. Patients were eligible for inclusion as age-matched controls if they were treated for lymphoma, received combination chemotherapy, and did not develop therapy-related myeloid neoplasms after at least 5 years of follow-up. We used molecular barcode sequencing of 32 genes on the pretreatment peripheral blood samples to detect clonal haemopoiesis. For cases, we also used targeted gene sequencing on bone marrow samples and investigated clonal evolution from clonal haemopoiesis to the development of therapy-related myeloid neoplasms. To further clarify the association between clonal haemopoiesis and therapy-related myeloid neoplasm development, we also analysed the prevalence of clonal haemopoiesis in an external cohort of patients with lymphoma who were treated in a randomised trial of front-line chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without melatonin. This trial was done at MD Anderson Cancer Center between 1999 and 2001 (protocol number 98-009).

Findings

We identified 14 cases and 54 controls. Of the 14 cases, we detected clonal haemopoiesis in the peripheral blood samples of ten (71%) patients. We detected clonal haemopoiesis in 17 (31%) of the 54 controls. The cumulative incidence of therapy-related myeloid neoplasms in both cases and controls at 5 years was significantly higher in patients with clonal haemopoiesis (30%, 95% CI 16–51) than in those without (7%, 2–21; p=0·016). In the external cohort, five (7%) of 74 patients developed therapy-related myeloid neoplasms, of whom four (80%) had clonal haemopoiesis; 11 (16%) of 69 patients who did not develop therapy-related myeloid neoplasms had clonal haemopoiesis. In the external cohort, the cumulative incidence of therapy-related myeloid neoplasms at 10 years was significantly higher in patients with clonal haemopoiesis (29%, 95% CI 8–53) than in those without (0%, 0–0; p=0·0009). In a multivariate Fine and Gray model based on the external cohort, the presence of clonal haemopoiesis significantly increased the risk of therapy-related myeloid neoplasm development (hazard ratio 13·7, 95% CI 1·7–108·7; p=0·013).

Interpretation

Preleukaemic clonal haemopoiesis is common in patients with therapy-related myeloid neoplasms at the time of their primary cancer diagnosis and before they have been exposed to treatment. Our results suggest that clonal haemopoiesis could be used as a predictive marker to identify patients with cancer who are at risk of developing therapy-related myeloid neoplasms. A prospective trial to validate this concept is warranted.

Funding

Cancer Prevention Research Institute of Texas, Red and Charline McCombs Institute for the Early Detection and Treatment of Cancer, NIH through MD Anderson Cancer Center Support Grant, and the MD Anderson MDS & AML Moon Shots Program.

Introduction

Therapy-related myeloid neoplasms are secondary malignancies that develop in patients who have received cytotoxic chemotherapy, ionising radiotherapy, or both.1, 2 The cumulative incidence of therapy-related myeloid neoplasms is roughly 1–10% over about 10 years, with incidence varying substantially by cancer type and treatment regimen (highest incidence in patients with lymphoma).3, 4, 5 Therapy-related myeloid neoplasms usually develop 3–8 years after exposure to initial treatment, are often associated with poor prognostic features such as complex cytogenetics and TP53 mutations, and respond poorly to conventional chemotherapies.⁶ Patients with therapy-related myeloid neoplasms have poor outcomes, with estimated median overall survival of 8–10 months and 5-year overall survival of 10–20%.6, 7, 8, 9

Research in context

Evidence before this study

We searched PubMed for reviews and research articles published in English from May 8, 1980, to June 1, 2016, using the keywords “therapy-related myeloid neoplasms”, “t-MNs”, “t-MDS”, “t-AML”, and “risk factors”. This search yielded about 1000 results. Several treatment-related risk factors have been reported to be associated with therapy-related myeloid neoplasms, including exposure to alkylating agents, topoisomerase II inhibitors, and high-dose chemotherapy with autologous stem-cell transplantation. By contrast, little is known about patient-specific risk factors. Older age was shown to increase the risk of therapy-related myeloid neoplasms. Several germline polymorphisms have also been associated with this risk, but none have been validated. As such, no predictive biomarkers exist for therapy-related myeloid neoplasms.

Added value of this study

Our results show that preleukaemic clonal haemopoiesis was common in patients with cancer who subsequently developed therapy-related myeloid neoplasms, and was detectable at the time of their primary cancer diagnosis, before they had received any therapy. Patients with preleukaemic clonal haemopoiesis had a significantly higher risk of developing therapy-related myeloid neoplasms than did those without clonal haemopoiesis.

Implications of all the available evidence

Patients with cancer who have preleukaemic clonal haemopoiesis are at increased risk of developing therapy-related myeloid neoplasms. Clonal haemopoiesis might function as a potential biomarker for risk prediction and early detection of therapy-related myeloid neoplasms and could be considered as a future therapeutic target to prevent the development of therapy-related myeloid neoplasms.

Exposure to particular types of chemotherapy is a known treatment-related risk factor for therapy-related myeloid neoplasms. For example, therapy-related myeloid neoplasms occur more frequently in patients who receive alkylating agents (eg, cyclophosphamide) and topoisomerase II inhibitors (eg, etoposide) than in those who receive antimetabolites or taxanes.4, 10, 11 Use of granulocyte colony-stimulating factor (G-CSF) in patients treated for cancer is associated with the risk of therapy-related myeloid neoplasms.12, 13 High-dose chemotherapy followed by autologous stem-cell transplantation can also increase the risk of therapy-related myeloid neoplasms in patients with lymphoma.¹⁴ Furthermore, a dose-dependent relationship exists between the risk of therapy-related myeloid neoplasms and cumulative doses of platinum exposure in patients with ovarian cancer.¹⁵ By contrast, little is known about patient-related risk factors for therapy-related myeloid neoplasms. Older age has been shown to increase the risk of therapy-related myeloid neoplasms, and although germline polymorphisms have been reported to be associated with risk, none have been validated.6, 14, 16, 17, 18, 19, 20, 21 In patients with lymphoma who have undergone autologous stem-cell transplantation, a gene expression signature of 38 genes in pretransplant samples and accelerated shortening of telomere length in post-transplant myeloid cells have been shown to be associated with therapy-related myeloid neoplasms.22, 23 Despite these efforts, no predictive biomarker or risk-stratification approach exists for the early detection or prevention of therapy-related myeloid neoplasms.

Preleukaemic mutations, such as mutations in DNMT3A, TET2, and ASXL1, can be detected in peripheral blood samples from healthy individuals—referred to as clonal haemopoiesis of indeterminate potential (CHIP).24, 25, 26, 27, 28 Compared with individuals without CHIP, those with CHIP had an increased risk of developing haematological neoplasms.25, 26 CHIP has also been identified in about 2% of patients with solid tumours who were analysed as part of The Cancer Genome Atlas (TCGA).²⁹ Furthermore, preleukaemic TP53 mutations were detectable in peripheral blood samples that were obtained 5–6 years before patients developed therapy-related myeloid neoplasms.³⁰

Overall, these data suggest that therapy-related myeloid neoplasms arise from antecedent clonal haemopoiesis and that detection of clonal haemopoiesis at the time of cancer diagnosis could help in the identification of patients with cancer who are at increased risk of developing subsequent therapy-related myeloid neoplasms. Therefore, in this study, we aimed to identify whether patients with cancer who have clonal haemopoiesis are at increased risk of developing therapy-related myeloid neoplasms.

Section snippets

Study design and participants

We designed a case-control study to compare the prevalence of clonal haemopoiesis between patients with cancer who developed therapy-related myeloid neoplasms (cases) and patients who did not develop therapy-related myeloid neoplasms (controls).

For cases, we searched our clinical database at the Department of Leukemia of The University of Texas MD Anderson Cancer Center (Houston, TX, USA). This database started to collect data in 1965 and includes data from 40 000 patients who have consented

Results

From our initial database search, we identified 169 patients with therapy-related myeloid neoplasms (figure 1). Of these 169 patients, 14 had both bone marrow samples from the time of the diagnosis of therapy-related myeloid neoplasm and peripheral blood samples that were previously obtained at the time of primary cancer diagnosis before they were exposed to chemotherapy or radiotherapy (figure 1). The remaining 155 patients with therapy-related myeloid neoplasms did not have pretreatment

Discussion

In this study, preleukaemic driver mutations were detectable as clonal haemopoiesis at the time of primary cancer diagnosis in ten of 14 patients who later developed therapy-related myeloid neoplasms. Although clonal haemopoiesis was detected in control patients who did not develop therapy-related myeloid neoplasms, the prevalence was significantly lower than in cases. This finding was also supported by analysis of an external cohort in which the presence of clonal haemopoiesis significantly

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^†: These authors contributed equally

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ArticlesPreleukaemic clonal haemopoiesis and risk of therapy-related myeloid neoplasms: a case-control study

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

Blood

Chem Biol Interact

Blood

Blood

Clin Lymphoma Myeloma Leuk

Blood

Blood

Blood

Blood

Blood

Leuk Res

Cancer Cell

Blood

Cell Rep

Semin Oncol

Cell Stem Cell

Therapy-related leukemia and myelodysplasia: susceptibility and incidence

Haematologica

The epidemiology of second primary cancers

Cancer Epidemiol Biomarkers Prev

Articles
Preleukaemic clonal haemopoiesis and risk of therapy-related myeloid neoplasms: a case-control study